Human cytomegalovirus (CMV) is a ?-herpesvirus with a seroprevalance of 60-90% among the population that can cause morbidity and mortality in immuno-compromised individuals. Common manifestations of CMV disease that occur in immunocompromised hosts include neuronal defects in infants and gastrointestinal disorders, pneumonia, CMV syndrome, and end-organ disease in transplant recipients. Remarkably, CMV is the leading cause of birth defects affecting up to 2.5% of newborns worldwide and is linked to early vascular damage because it can infect endothelial cells and macrophages. The ability of CMV to infect multiple cell types such as endothelial cells, epithelial cells, and monocytes is essential for viral dissemination and proliferation within the host. CMV entry requires viral binding to the cell surface, post-binding receptor clustering followed by viral fusion with cell membranes and release of capsid in the cytosol. The viral fusion event can occur at the cell surface as well as in a pH-dependent manner within endosomes of epithelial and endothelial cells. Even though the epidermal growth factor receptor and the platelet-derived growth factor receptor-? have been implicated in virus entry, the given complexity of CMV entry would require many additional cell factors to ensure a successful virus infection. We hypothesize that unique cell surface proteins are essential for a successful virus infection by playing important roles in virus binding, endocytosis, fusion, trafficking to nucleus, and viral gene expression. Thus, we plan to utilize a recently developed functional screen for neutralizing antibodies to discover epithelial and endothelial cell factors important for CMV entry. The identification and characterization of the antibody's target will uncover novel entry factors and provide a molecular understanding of the early phase of a virus infection. Also, these reagents will allow for the simultaneous development of anti-CMV therapeutics that can be used to limit CMV disease in immuno- compromised patient at high-risk for CMV-associated disorders.